Cigarette smoking is strongly correlated with onset of lung cancer and statistically more than 90% of lung cancer patients are smokers. However, lung cancer caused by second-hand smoking remains unknown. Nicotine is a major component of cigarettes and exists at high concentrations in the bloodstream of smokers. Nicotine-based products are widely used to aid smoking cessation and to treat patients clinically with chronic pain. Studies have shown that nicotine binds to nicotine acetylcholine receptors (nAChRs) and further activates several mitogen-related signaling pathways in various types of cells including lung epithelial and cancer cells and vascular endothelial cells. The anti-apoptotic activity of Bcl-2 is also induced by nicotine treatment. We demonstrated that nicotine activates Ras and protein kinase C (PKC) pathways, leading to the disruption of cell growth restriction. However, the mechanisms of nicotine in the onset or development of lung cancer remain to be elucidated. Therefore, our long-term objective of the proposal is to study the role of nicotine in lung carcinogenesis. Such study will identify novel components in nicotine-mediated signaling pathways and will help modifying the current usage of nicotine. The central hypothesis of the proposal is that nicotine acts as a potential carcinogen that can mobilize intracellular growth-related signal pathways and antagonize apoptotic signaling, which creates a permissive environment for tumorigenesis. The specific aims to test the hypothesis are: 1) to investigate the mechanisms of nicotine-mediated cell growth promotion; 2) to determine how nicotine exposure perturbs G1 cell cycle checkpoint; 3) to study the molecular mechanisms of nicotine-mediated anti-apoptotic action. Mouse or rat lung epithelial and various human lung cancer cells will be used in the proposed experiments. Our understanding of nicotine will not only offer a cautionary stance for the therapeutic use of this compound, but also help developing new stratigies for treating nicotine addiction or chronic pain cessation.